Lymphedema is a chronic disabling condition which results in swelling of the extremities. Patients with lymphedema suffer from recurrent local infections, physical impairment, social stigmatization, and may be at increased risk of developing cancers such as lymphangiosarcoma. This is an incurable disorder requiring lifelong attention. Despite a general understanding of the pathophysiology resulting in the development of lymphedema, prior to our work essentially nothing had been known about the genetic basis of primary lymphedema. Understanding the genetic basis for the subset of inherited lymphedemas would be a major advance in robust classification of lymphatic disorders. Genotypic classification would serve as a basis for the evaluation of careful treatment trials. We have linked chromosomal region 5q34-35 to, the lymphedema phenotype and provided evidence for allelic and locus heterogeneity for hereditary lymphedema. We identified and expressed mutations in VEGFR-3 which demonstrate it as a causative gene for hereditary lymphedema. We propose to further characterize the genetic basis of hereditary lymphedema by 1) mutation analysis of VEGFR-3 and other contributory genes; 2) linkage studies, positional and biochemical candidate gene analysis to identify new contributory loci to the lymphedema phenotype: 3) in vitro functional studies to establish the causal relationship between mutation and phenotype; 4) genetic epidemiologic studies to assess the role of specific lymphedema loci in predisposing individuals to secondary lymphedema. These studies will ultimately lead to a better understanding of the developmental biology of the lymphatic system, and provide a means of identifying high risk individuals in lymphedema families, as well as the normal population.